FSU Grand Rounds12/13/2018
Funded by NIDA, NIAAA
National Survey on Drug Use & Health (NSDUH), 2013
NSDUH, 2013
NSDUH, 2015
2015
NSDUH, 2017
2015
2017
0123456789
10
2002 2014
PregnantNonpregnant
PAST MONTH MARIJUANA USE AMONG PREGNANT AND NONPREGNANT WOMEN
Brown et al., JAMA 2017
Perc
ent
0
2
4
6
8
10
12
14
16
12-17 yrs 18-25 yrs ≥ 25 yrs
PAST MONTH MARIJUANA USE AMONG PREGNANT WOMEN BY AGE
Volkow et al., Annals Int Med 2017
Perc
ent
INCREASING POTENCY OF MARIJUANA
INCREASING POTENCY OF MARIJUANA
2012
LEGALIZATION OF MARIJUANA
cnn.com
wcvb.com
INCREASING LEGALIZATION OF MARIJUANA
INCREASING LEGALIZATION OF MARIJUANA
CHALLENGES IN STUDYING PRENATAL MARIJUANA EXPOSURE
• Theoretical model• Assessment of exposure• Assessment of outcomes• Assessment of covariates• Evaluating prenatal vs. current environmental
influences
CHALLENGES IN STUDYING PRENATAL MARIJUANA EXPOSURE
• Theoretical model• Assessment of exposure• Assessment of outcomes• Assessment of covariates• Evaluating prenatal vs. current environmental
influences
HOW TO MEASURE DRUG USE?
PARAMETERS FOR MEASURINGSUBSTANCE USE
• Quantity• Frequency• Duration
HOW MUCH ALCOHOL IS IN A DRINK?
12 oz beer = 5 oz wine = shot of liquor
Each contains 0.5 oz of alcoholNIAAA
WHAT IS MARIJUANA?
Cannabis Sativa plant
500+ compounds; 100+ cannabinoids
Mechoulam & Hanuš, 2000
Main psychoactive ingredient is ∆9-tetrahydrocannabinol (∆9-THC)
JOINTS
BLUNTS
CIGARS, CIGARILLOS
PIPES, BONGS
Image courtesy of the Weed Street Journal
MARIJUANA WAX
MARIJUANA INTOXICATION
Initially, increase in arousal, excitement, vasodilation, tachycardia, heightened senses
Later, euphoria, sedation, relaxation; at high doses, perceptual changes, paranoia, anxiety attacks
Post-intoxication involves low energy, decreased motivation, binge eating, sedation
Side effects include memory impairments, impaired motor coordination, poor judgment, erratic behavior, reduced reaction time
NEUROBIOLOGY OF MARIJUANA
Guzman (2003), Nat. Reviews Cancer
Endocannabinoids bind to cannabinoid receptors (CB1 and CB2)
CB1 receptors are GPCRs and are Gi/ocoupled
Activation of CB1 typically decreases vesicular neurotransmitter release
NEUROBIOLOGY OF MARIJUANA
Elliot Gardner - Neuroscience Letters, 1991, 129: 1872-79
DA
in N
ucle
us A
ccum
bens
CANNABINOID EFFECTS ON DOPAMINE TRANSPORT
Transl Psychiatry. 2016 May; 6(5): e809
Stanwood group has described protective effects of GLP-1 receptor agonists on cocaine reward.
This is due to GLP-1 receptors blocking the endocannabinoid 2-AG, which then retrogradely alter the trafficking dynamics of thedopamine transporter (the substrate for cocaine).
ENDOCANNABINOIDS AND NEURODEVELOPMENT
In human, CB1 receptors are detectable by week 14 of gestation
Many possiblemechanisms
through which drugs can alter fetal
neurodevelopment
ANIMAL MODELS OF PRENATALMARIJUANA / THC / CANNABINOIDS
• Generally speaking, the animal literature has been poorly developed!
• Multiple doses, duration, and routes of administration have been used with little consistency.
• Nevertheless, several recent studies of note.
Impaired performance on a skill pellet-reaching task
Transiently altered CB1 receptors during prenatal development
Deficits restored by normalization of CB1 receptors on excitatory neurons!
Reduced hippocampal CCK-INT number and complexity
Compromised CCK-INT-mediated feedforward and feedback inhibition
Altered socialbehavior
Pittsburgh Maternal Health Practices & Child Development Project Cohorts
Alcohol Use During Pregnancy
NIAAAN. Day
Prenatal MarijuanaExposure
NIDAN. Day
Teenage PrenatalTobacco UseNIAAA/NIDAM. Cornelius
Prenatal CocaineUse
NIDAG. Richardson
Core Data SetsInstrumentsPersonnelAnalyses
PRENATAL PHASES4th prenatal month 7th prenatal month 24-48 hrs post-delivery
1st trimester 2nd trimester 3rd trimester
STUDY DESIGN
4TH PRENATAL MONTH 1982-19857TH PRENATAL MONTH
DELIVERY (N = 763 combined cohort)8 MONTHS18 MONTHS
10 YEARS
16 YEARS
3 YEARS6 YEARS
14 YEARS
22 YEARS
METHODS OF DETECTION
• Biological markers
• Interviews
• Self-report questionnaires
BIOLOGICAL MARKERS
Window of detection varies with:
• Type of assay
• Drug
• Chronicity of use
DETECTION OF MARIJUANA USE
DETECTION OF MARIJUANA USE
• Substantial evidence of greater detection of marijuana use by self-report/interview methods than by biological assays
Fendrich et al., 2004; Gray et al., 2010; Richardson et al., 2006
DETECTION OF MARIJUANA USE
Positive urine screen, reported use on interview:
95%
Reported use on interview, negative urine screen:
40%
Usual
Marijuana 37%
Cocaine 47%
IMPORTANCE OF QUESTION FORMAT
Richardson, Huestis, Day, 2006
Usual Maximum Minimum
Marijuana 37% 45% 17%
Cocaine 47% 50% 3%
IMPORTANCE OF QUESTION FORMAT
Richardson, Huestis, Day, 2006
PATTERN OF MATERNAL MARIJUANA USE
0102030405060708090
100
Yearprior
1st trim. 3rd trim. 18 mos 6 yrs 14 yrs 22 yrs
PER
CEN
T
None: 0 joints/day Light: <1 joint/day Heavy: 1+ joints/day
PATTERN OF MATERNAL ALCOHOL USE
0
10
20
30
40
50
60
70
80
Yearprior
1st trim. 3rd trim. 18 mos 6 yrs 14 yrs 22 yrs
PER
CEN
T
None: 0 drinks/day Light: <1 drink/day Heavy: 1+ drinks/day_
PATTERN OF MATERNAL TOBACCO USE
0
10
20
30
40
50
60
1st trim. 3rd trim. 18 mos 6 yrs 14 yrs 22 yrs
PER
CEN
T
None: 0 cigarettes/day Light: < 1 pack/day Heavy: 1+ packs/day_
WHAT IS ASSOCIATED WITH PRENATAL MARIJUANA USE?
CHARACTERISTICS ASSOCIATED WITH 1ST
TRIMESTER MARIJUANA USE
No Use Heavy Use* Significance
Maternal age 22.9 23.2 ns(yrs)
Education (yrs) 12.0 11.8 ns% Caucasian 53.8 22.3 p < .01% Married 37.6 18.4 p < .01Family income 56.1 71.3 p < .05(% < $400/month)
*≥ 1 joint/dayDay et al., 1991
USE OF OTHER SUBSTANCES BY FIRST TRIMESTER MARIJUANA USE
0102030405060708090
Alcohol Tobacco Other Drugs
No PMEHeavy PME**≥1 joint/day
PER
CEN
T
1st trimester drug use
EFFECTS OF PRENATAL MARIJUANAMATERNAL HEALTH COHORT
Birth 3 years 6 years 10 years 14 years 22 years
GROWTH ___________________________________________________________________
BEHAVIOR________________________________________________________________
COGNITIVE
EFFECTS ON COGNITION
RELATION BETWEEN PME & 6 YEAR IQ
80
85
90
95
100
105
Overall IQ ST Memory Verbal
No PMEHeavy PME**≥1 joint/day
Stan
ford
-Bin
et S
core
s
Goldschmidt et al., 2008
Nomarijuana
use
Lighta
marijuana use
Heavyb
marijuana use
Significance
No adjustments 95.9 93.6 89.0 .001
Goldschmidt et al., 2004a < 1 joint/day; b ≥ 1 joint/day
IMPORTANCE OF CONTROL OF COVARIATES10-year PIAT reading comprehension
Nomarijuana
use
Lighta
marijuana use
Heavyb
marijuana use
Significance
No adjustments 95.9 93.6 89.0 .001
Adjust for:Home environment (HOME)
95.6 93.7 90.2 .01
Goldschmidt et al., 2004a < 1 joint/day; b ≥ 1 joint/day
IMPORTANCE OF CONTROL OF COVARIATES10-year PIAT reading comprehension
Nomarijuana
use
Lighta
marijuana use
Heavyb
marijuana use
Significance
No adjustments 95.9 93.6 89.0 .001
Adjust for:Home environment (HOME)
95.6 93.7 90.2 .01
HOME, education 95.5 93.9 90.1 .01
Goldschmidt et al., 2004a < 1 joint/day; b ≥ 1 joint/day
IMPORTANCE OF CONTROL OF COVARIATES10-year PIAT reading comprehension
Nomarijuana
use
Lighta
marijuana use
Heavyb
marijuana use
Significance
No adjustments 95.9 93.6 89.0 .001
Adjust for:Home environment (HOME)
95.6 93.7 90.2 .01
HOME, education 95.5 93.9 90.1 .01
HOME, education, race
95.1 94.1 91.5 ns
Goldschmidt et al., 2004a < 1 joint/day; b ≥ 1 joint/day
IMPORTANCE OF CONTROL OF COVARIATES10-year PIAT reading comprehension
EFFECTS ON BEHAVIOR
RELATION BETWEEN PME & 10 YEAR BEHAVIOR
0
5
10
15
20
25
30
Delinquent Aggressive
No PMEHeavy PME*
*≥1 joint/day
Perc
ent a
bove
bor
derli
ne
clin
ical
cut
off
Teacher Reported Behavior Goldschmidt et al., 2000
OFFSPRING SUBSTANCE USE ACROSS TIME
0102030405060708090
100
10 years 14 years 22 years
AlcoholTobaccoMarijuana
% use
P < .001
Sonon et al., 2015
RELATION BETWEEN PME & 22 YEAR OFFSPRING MARIJUANA USE
0
10
20
30
40
50
60
70
No PME Any PME
No use
≥ 3 times/wk%
use at 22 yrs
RELATION BETWEEN PME & PSYCHOTIC SYMPTOMS AT 22 YEARS
0
10
20
30
40
50
60
70
PS = 0 PS ≥ 3
No PMEHeavy PME*
*≥1 joint/day
Perc
ent
Psychotic symptoms Day et al., 2015
Adolescent marijuana exposure increases susceptibility to develop psychosis and other neuropsychiatric conditions. Even earlier exposures may do the same (or worse?).
EFFECTS OF PRENATAL MARIJUANAMATERNAL HEALTH COHORT
Birth 3 years 6 years 10 years 14 years 22 years
GROWTH length -- -- -- -- --___________________________________________________________________
BEHAVIOR sleep changes impulsivity activity, delinquency, marijuana use,inattention, marijuana use psychotic sx,impulsivity, arrestsdelinquency,depression
_________________________________________________________________
COGNITIVE IQ, IQ, memory,memory memory achievement achievement
• Effects of prenatal marijuana exposure on
behavior and cognition consistent across phases
(and studies)
• Increased risk of marijuana use in offspring
• Pattern of effects consistent with teratologic model
and mechanisms
CONCLUSIONS
IMPLICATIONS
• Different types/patterns of prenatal marijuana use
• Co-use of marijuana and tobacco is common
• Consider other characteristics associated with prenatal drug use
• Non-judgmental communication is important
• Understand woman’s belief system
MATERNAL HEALTH PROJECT
3 years 6 years 10 years 14 years
Overall IQ- Short term memory- Verbal
Day et al., 1994
Overall IQ- Short-term memory-Verbal-Quantitative
Goldschmidt et al., 2008
Achievement:- Reading- Spelling
Memory – overall;- visual
Goldschmidt et al., 2004;Richardson et al., 2002
Achievement:- Reading- Total
Goldschmidt et al., 2012
EFFECTS OF PRENATAL MARIJUANA EXPOSURE ON COGNITIVE DOMAINS
EFFECTS OF PRENATAL MARIJUANA EXPOSURE ON BEHAVIOR
6 years 10 years 14 years 22 years
Impulsivity Inattention ImpulsivityActivity
Psychoticsymptoms
Delinquency Delinquency Maladaptive adult roles
Depression Marijuana use Marijuana use
Leech et al., 1999 Goldschmidt et al., 2000;Gray et al., 2005
Day et al., 2006, 2011 Day et al., 2015;Goldschmidt et al., 2016;Sonon et al., 2015